Alzheimer's disease is characterized by profound progressive neurodegeneration that has devastating effects not only on patients but also on families and caregivers. At present, there is no cure for Alzheimer's disease, and current treatments provide modest delay in progression in a subset of all patients. It is essential to identify pathways that can modulate the development of toxicity in order to develop new treatments. Studies of families with genetically inherited neurodegenerative disease, mouse models of Alzheimer's disease, and cell culture models implicate the amyloid beta peptide, the amyloid precursor protein from which amyloid beta is derived, and the microtubule binding protein tau in pathways that lead to loss of cognitive function. Hirano bodies are actin-rich structures that appear in the brain in increased numbers in association with many conditions including Alzheimer's disease. The physiological function of Hirano bodies is not known. However, it is known that Hirano bodies accumulate COOH terminal regions of the amyloid precursor protein and also tau. Therefore, Hirano bodies could influence the progression of Alzheimer's disease. We have recently developed cell culture models and a transgenic mouse model for studies of Hirano bodies. The long term goal of this project is to understand the impact of Hirano bodies on the progression of disease. The goal of this proposal is to test the hypothesis that Hirano bodies either promote or protect from development of pathology in Alzheimer's disease. To achieve this objective, a mouse model of Hirano bodies will be crossed with transgenic Alzheimer's model mice that have symptoms of neurodegeneration induced either by amyloid precursor protein or tau. The outcomes will be assessed using immunohistochemistry, electrophysiology, and behavioral studies to assess the effect of Hirano bodies on development of neuropathology and cognitive decline in vivo. These studies will critically test the hypothesis that Hirano bodies can modulate neurotoxicity in Alzheimer's disease. In addition, the studies will reveal whether Hirano bodies can affect toxicity initiated by pathways involving amyloid precursor protein and/or tau. If the results show that Hirano bodies can modulate the progression of this disease, then pathways involved in formation or degradation of Hirano bodies would be identified as novel targets for drug development to treat Alzheimer's disease. PUBLIC HEALTH RELEVANCE: New drug treatments are urgently needed for treatment of Alzheimer's disease, since Alzheimer's disease has a major impact on the health of millions of disease victims and family members, and because current therapies are only marginally effective. To identify novel targets for drug development, it is essential to determine the events that damage brain cells in Alzheimer's disease, as well as pathways that can regulate this process. This project seeks to determine whether structures called Hirano bodies that are present in increased numbers in the brain of Alzheimer's patients can affect the progression of Alzheimer's disease, and whether pathways leading to formation or degradation of Hirano bodies are novel candidates for drug development to treat Alzheimer's disease.